CN103919794A - Application of ginsenoside Rh1 in preparation of drugs for improving glucocorticoid resistance - Google Patents
Application of ginsenoside Rh1 in preparation of drugs for improving glucocorticoid resistance Download PDFInfo
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- CN103919794A CN103919794A CN201310011400.8A CN201310011400A CN103919794A CN 103919794 A CN103919794 A CN 103919794A CN 201310011400 A CN201310011400 A CN 201310011400A CN 103919794 A CN103919794 A CN 103919794A
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Abstract
The present invention discloses a new medical use of ginsenoside Rh1, and specifically relates to an application of ginsenoside Rh1 in preparation of drugs for improving glucocorticoid resistance. According to the present invention, in vitro and in vivo study results show that: with the ginsenoside Rh1, hormone resistance caused by long term and high dose use of dexamethasone can be significantly improved so as to improve the anti-inflammatory effect of dexamethasone, the action is related to up-regulation of the glucocorticoid receptor, and blood sugar increase can not be caused, such that the application prospects for preparation of the drugs for improving glucocorticoid resistance are provided.
Description
Technical field
The present invention relates to medical technical field, be specifically related to the new medical use of ginsenoside Rh1.
Background technology
Glucocorticoid is widely used in treating various inflammation and immune correlated disease, such as asthma, rheumatoid arthritis and some autoimmune diseasees, but a part of patient is insensitive to treating, even in the situation that using heavy dose of hormone, still treatment is shown as to hyposensitivity, or insensitive.The patient of other inflammation class disease, as chronic obstructive pulmonary disease, interstitial pneumonia, acute respiratory distress disease, cystic fibrosis of the pancreas, great majority all show as hormonal resistance.Because this class chronic inflammatory disease class disease is clinical very common, and sickness rate is still rising year by year, therefore, even resists if patient shows as hyposensitivity to hormone therapy, is just difficult to obtain the effective treatment, and also can increase accordingly for medical expense.So the medicine that improves hormonal resistance has very wide market prospect, the research and development of this indication medicine are one of focuses of new drug development.
The biological effect of glucocorticoid mainly relies on glucocorticoid receptor (GR) mediation performance, but can to regulate by negative feedback be that the quantity of glucocorticoid receptor (GR) reduces to the use hormone of long-term, high-dose, affinity reduction.Now there are some researches show, it is that hormonal resistance one of the main reasons occurs that glucocorticoid receptor (GR) reduces.Therefore, search out a kind of safe and effectively, can raise glucocorticoid receptor (GR), improve the medicine of hormonal resistance, for improving clinically curative effect, to reduce medical treatment cost all significant.
Ginsenoside Rh1 (20S-ginsenoside Rh1) (structural formula is shown in formula 1) is present in ginseng crude drug on a small quantity, studies at present lessly, mainly has myocardial damage reparation, inhibition tumor cell Invasion and Metastasis and anti-allergic effects.Ginsenoside Rh1 is for the adjusting of glucocorticoid receptor (GR), and there is not yet bibliographical information in the research improving aspect hormonal resistance.
The structural formula of formula 1. ginsenoside Rh1s
Summary of the invention
Technical problem to be solved by this invention is the new medical use that proposes ginsenoside Rh1, particularly, is to propose ginsenoside Rh1 in the application improving in glucocorticoid resistance.
The present invention realizes by following technical scheme.Set up two schemes of external glucocorticoid long-term treatment and short term therapy, give dexamethasone and ginsenoside Rh1 therapeutic alliance.Find:
1, in long-term treatment regimen, the antiinflammatory action of dexamethasone reduces, and ginsenoside's Combined with Dexamethasone can significantly be improved the antiinflammatory curative effect of hormone.
2, ginsenoside Rh1 can significantly reduce in vitro induced by dexamethasone generate glyconeogenesis close build enzyme (G-6-P and PEPCK) express.
3, the mouse arthritis model that application Freund adjuvant causes, ginsenoside Rh1 Combined with Dexamethasone is all obviously better than alone Dexamethasone group in antiinflammatory degree with on onset time, and can not cause blood sugar increasing.
The present invention proves that by pharmacological research in external, body ginsenoside Rh1 can improve hormonal resistance, improves dexamethasone antiinflammatory curative effect, alleviates the blood sugar increasing side effect that dexamethasone causes simultaneously.For needing long-term, high-dose to use some inflammation class diseases of glucocorticoid treatment, such as asthma, rheumatoid arthritis, chronic obstructive pulmonary disease, interstitial pneumonia, acute respiratory distress disease, cystic fibrosis of the pancreas etc., there is good use value, can alleviate patient's misery, improve because heavy dose of side effect that uses hormone to cause, shorten treatment time, reduce medical treatment cost.
Brief description of the drawings
(note: drug level dosage unit is μ M, detection method is real time RT PCR to the figure that affects of the inflammatory reaction that Fig. 1 is ginsenoside Rh1 Combined with Dexamethasone on TNF α induction.Experiment repeats more than 3 times.
*p<0.05,
**p<0.01versus?TNF?group;#p<0.05,##p<0.01versus?DEX?group）。
Fig. 2 is that on the figure that affects of glucocorticoid receptor (GR), (note: A figure is glucocorticoid receptor protein expression, adopts Western-blot to detect to ginsenoside Rh1, and B figure is acceptor binding force, adopts radioactive ligand to detect.
*p<0.05,
**p<0.01versus?Control,#p<0.01versus?DEX?group）。
Fig. 3 is that on the figure that affects of G-6-P and PEPCK, (note: G-6-P and PEPCK adopt real time RT PCR to detect to ginsenoside Rh1, more than experiment in triplicate.
*p<0.01versus?Control,#p<0.01versus?DEX?group）。
Fig. 4 be glucocorticoid receptor (GR) in the impact of ginsenoside Rh1 on the inflammatory reaction of CIA mice and body adjusting figure (note: figure A is the scoring of mice inflammation,
*p<0.05,
*p<0.01compared with PBS, #p<0.05compared with DEX, figure B is that GRmRNA expresses, real time RT PCR detects,
*p<0.05,
*p<0.01compared with blank, ##p<0.01compared with DEX).
Fig. 5 be ginsenoside Rh1 in vivo on blood glucose affect figure (note:
*p<0.01versus blank; #p<0.01versus DEX group).
Detailed description of the invention
Below in conjunction with the drawings and specific embodiments, further set forth the present invention.These embodiment are interpreted as being only not used in and limiting the scope of the invention for the present invention is described.After having read the content of the present invention's record, those skilled in the art can make various changes or modifications the present invention, and these equivalences change and modification falls into the scope of the claims in the present invention equally.
The ginsenoside Rh1 using in following examples of the present invention can extract according to usual method from ginseng crude drug, also can buy from commercial channel (as Yuan Ye bio tech ltd, Shanghai, specification is HPLC >=98%, and 20mg/ props up).
Embodiment 1(ginsenoside Rh1 improves hormonal resistance, improves the in vitro study of dexamethasone antiinflammatory curative effect)
(1) materials and methods
1, cell strain: mouse monokaryon-macrophage (RAW264.7), purchased from ATCC.Primary mouse liver cell separates from BALB/C mice.Above-mentioned cell strain is 5%CO by the DMEM culture medium that contains 10% hyclone at 37 DEG C, volume fraction
2, complete cellar culture under saturated humidity condition, 48h changes culture medium, Growth of Cells reaches full while closing state, by 0.25% trypsin+0.02%EDTA had digestive transfer culture, 2～3d goes down to posterity 1 time, tests and selects exponential phase cell.
2, the impact of the inflammatory reaction of ginsenoside Rh1 on TNF α induction.
On 24 orifice plates respectively with 2 × 10
5with 1 × 10
5individual RAW264.7 cell bed board, after cell attachment, adds dexamethasone/ginsenoside Rh1+dexamethasone (dexamethasone concentration 10
-6m, ginsenoside Rh1 concentration is 10
-5m, 10
-6m, 10
-7m), respectively at adding TNF α (20ng/ml) effect 8h after 2h and 24h, add Trizol cell lysis, extract RNA, Realtime RT PCR detects inflammatory factor IL-6, IL-17, TNF α, MMP-1mRNA express.All establish 3 multiple holes for every group.
3, the impact of ginsenoside Rh1 on glucocorticoid receptor (GR).
On 6 orifice plates respectively with 2 × 10
6with 1 × 10
6individual cell bed board, after cell attachment, adds dexamethasone/ginsenoside Rh1+dexamethasone (dexamethasone concentration 10
-6m, ginsenoside Rh1 concentration is 10
-5m), respectively at adding TNF α (20ng/ml) effect 8h after 2h and 24h, collect cell, a part adds cell pyrolysis liquid extracting albumen, and quantitatively rear row Western-blot, detects protein expression.Another part carries out radioactive ligand and detects receptor-ligand affinity.
4, the impact of ginsenoside Rh1 on glyconeogenesis related gene G-6-P and PEPCK expression.
On 24 orifice plates with 1 × 10
5individual mouse primary hepatocyte bed board, after cell attachment, adds dexamethasone/ginsenoside Rh1+dexamethasone/ginsenoside Rh1 (dexamethasone concentration 10
-6m, ginsenoside Rh1 concentration is 10
-5m), collect cell after 24h, extract RNA, Realtime RT PCR detects G-6-P and PEPCK mrna expression.All establish 3 multiple holes for every group.
(2) experimental result
1, ginsenoside Rh1 can improve hormonal resistance.
Dexamethasone is intervened IL-6, IL-17, TNF α and the MMP-1 that 2h can obviously suppress TNF secretion inducing in advance, but extends dexamethasone intervention time to the obviously inhibitory action of inflammatory factor secretion nothing to TNF induction of 24h; And by ginsenoside Rh1 and dexamethasone use in conjunction, no matter administration 2h or 24h, has obvious inhibitory action for inflammatory factor.Alone ginsenoside Rh1, without obvious antiinflammatory action (see figure 1).
2, ginsenoside Rh1 is by regulating glucocorticoid receptor (GR) to improve hormonal resistance.
Result shows, dexamethasone intervention 2h, and protein expression and affinity to glucocorticoid receptor (GR) all have no significant effect, but intervene 24h, show as the remarkable reduction of glucocorticoid receptor expression and affinity.And ginsenoside Rh1 can obviously improve the GR downward (see figure 2) causing after effects of dexamethasone 24h.
3, ginsenoside Rh1 is inhibited to the glyconeogenesis key enzyme of dexamethasone abduction delivering.
Although ginsenoside Rh1 has rise effect to glucocorticoid receptor (GR), but glyconeogenesis related gene G-6-P, PEPCK that Rh1 activates dexamethasone show as certain inhibitory action, and alone ginsenoside Rh1 does not affect (see figure 3) to G-6-P, PEPCK.
The mouse arthritis therapeutical effect that embodiment 2(ginsenoside Rh1 Combined with Dexamethasone causes Freund adjuvant)
(1) materials and methods
1, laboratory animal
DBA-1 mice, in age in 6-8 week, is provided by Second Military Medical University, PLA's Experimental Animal Center.Sub-cage rearing under without special pathogen (SPF) condition, controls room temperature (23 ± 1 DEG C), and periodicity of illumination 12/12, freely looks for food, drinks water.
2, the preparation of main agents
Cattle typeⅡ Collagen and complete Freund's adjuvant mixture: get isopyknic cattle typeⅡ Collagen and complete Freund's adjuvant, fully mix emulsifying, until its standing 4h is still not stratified above.
3, model preparation and grouping administration
Modeling: every mice of modeling first day is taked root of the tail portion subcutaneous multi-point injection cattle typeⅡ Collagen and complete Freund's adjuvant mixture, every injection 100ul.Duplicate injection in the 21st day.Observe 2 times every day later, when finding that joint starts to occur after redness, mark (scoring is evaluated respectively by testing incoherent two research worker with this) according to mouse arthritis symptom, be chosen as 0～4 point according to symptom weight: 0 point, have no red and swollen; 1 point, what carpal joint was slight is red or swollen, or the inflammation of three toes; 2 points, exceed the inflammation of 3 toes or the redness of ankle joint or carpal joint moderate; 3 points, serious ankle joint and carpal inflammation; 4 points, comprise ankle joint widely and the carpal joint inflammation of all toes or newborn New bone formation.Every higher assessment of mice is 16 points.When more than 80% mouse arthritis scoring reaches 8 timesharing, carry out random packet.
Grouping: by successful modeling mice, arrange from high to low according to arthritis score, be divided into 8 groups, 3 every group.Produce random digit with Excel table, in every group random number maximum assign to A group, the minimum C group of assigning to, remaining assigns to B group.A group is PBS (PBS) group, and B group is dexamethasone (Dex) group, and C group is dexamethasone associating Rh1 medication (Dex+Rh1) group.
Administration: A group lumbar injection PBS200ul every day; B group lumbar injection dexamethasone every day (0.15mg/ml) 200ul; C organizes and injects dexamethasone (final concentration 0.15mg/ml) and Rh1(final concentration 2.5mg/ml every day), 200ul altogether.Successive administration 10 days.Mark every day according to mouse arthritis symptom.Separately establish 8 of Normal group mices (blank).
(2) experimental result
The degree of inflammation of the 3rd day ginsenoside Rh1 of administration and dexamethasone drug combination group, with model group comparison, obviously alleviate (P<0.05), and alone Dexamethasone group and model group relatively there is no difference (P>0.05), after this, the degree of inflammation of administration group all obviously alleviates (P<0.01), administration the 5th day, the degree of inflammation of Rh1 drug combination group is starkly lower than alone Dexamethasone group (P<0.05), to the 9th day, the mouse arthritis disease of administration group alleviated substantially.Ginsenoside Rh1 Combined with Dexamethasone is all better than alone Dexamethasone group in onset time of antiinflammatory and antiinflammatory degree.Detection Glucocorticoid Receptor is found, reducing appears in Dexamethasone group glucocorticoid receptor (GR), and use in conjunction ginsenoside Rh1, can improve Glucocorticoid Receptor (P<0.01), this may be better than the relevant (see figure 4) of alone Dexamethasone group with its antiphlogistic effects.In addition, there is blood sugar increasing in alone Dexamethasone group, and use in conjunction Rh1 has no significant effect (see figure 5) to blood glucose.
The preparation of embodiment 3(ginsenoside Rh1 tablet)
Get ginsenoside Rh1 50g, hydroxypropyl emthylcellulose 10g, microcrystalline Cellulose 50g, cross-linking sodium carboxymethyl cellulose 5g, mix, add appropriate 60% ethanol to make soft material, cross 24 mesh sieves and granulate, 50 DEG C are dried 2 hours, dried particles is crossed 30 mesh sieve granulate, add magnesium stearate 2.5g, mix, be pressed into respectively 1000.
The preparation of embodiment 4(ginsenoside Rh1 injection)
Take recipe quantity ginsenoside Rh1 powder, add in the injection Oleum Glycines of recipe quantity, fully mix, become oil phase; Take the injection phospholipid, glycerol of recipe quantity and the water for injection of appropriate (at least making phospholipid be dissolved as water completely), high-speed stirred after mixing, makes phospholipid be dissolved as water completely; Under high-speed stirred condition, oil phase is added in water with wire, after adding, then continue to stir 15 minutes, regulate pH to 6.5～7.0 with 0.1mol/L sodium hydroxide solution, then inject water to 1000ml, obtain milky colostrum; The colostrum making is moved into high pressure homogenizer, homogenize; Emulsion is with 0.45 μ m filtering with microporous membrane; By Emulsion embedding in suitable container; Put under 100 DEG C of conditions sterilizing 30 minutes, to obtain final product.
To sum up, ginsenoside Rh1 improves glucocorticoid resistance, improves hormone therapy, and effect is remarkable, and can improve the hyperglycemia side effect that hormone causes simultaneously, thereby has the DEVELOPMENT PROSPECT as hormons medication.
Claims (3)
1. ginsenoside Rh1 improves glucocorticoid resistance in preparation, improves the application in hormone therapy medicine.
2. the application of ginsenoside Rh1 in expression and the adhesion medicine of preparation rise glucocorticoid receptor (GR).
3. ginsenoside Rh1 alleviates glucocorticoid in preparation and causes the application in blood sugar increasing side effect medicine.
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Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107233571A (en) * | 2017-06-21 | 2017-10-10 | 中国人民解放军第三军医大学第附属医院 | The application of ICBP90 antibody and its expression inhibiting agent in the medicine for promoting glucocorticoid treatment effect is prepared |
| CN114272269A (en) * | 2021-12-22 | 2022-04-05 | 中国海洋大学 | Halocynthia Roretzi active dry powder and preparation method and application thereof |
-
2013
- 2013-01-11 CN CN201310011400.8A patent/CN103919794A/en active Pending
Non-Patent Citations (1)
| Title |
|---|
| 李俊: "人参皂苷Rh1改善糖皮质激素抵抗的实验研究", 《中国优秀硕士学位论文全文数据库医药卫生科技辑》 * |
Cited By (3)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN107233571A (en) * | 2017-06-21 | 2017-10-10 | 中国人民解放军第三军医大学第附属医院 | The application of ICBP90 antibody and its expression inhibiting agent in the medicine for promoting glucocorticoid treatment effect is prepared |
| CN107233571B (en) * | 2017-06-21 | 2021-02-02 | 中国人民解放军第三军医大学第一附属医院 | Application of ICBP90antibody and expression inhibitor thereof in preparation of medicine for promoting glucocorticoid treatment effect |
| CN114272269A (en) * | 2021-12-22 | 2022-04-05 | 中国海洋大学 | Halocynthia Roretzi active dry powder and preparation method and application thereof |
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Application publication date: 20140716 |